VP-16 undergoes O-demyelination to generate active intermediates that bind to proteins and DNA. The O-demethylation is P450-dependent. Peroxidases, such as horseradish or prostaglandin synthetase, also activate VP-l6 and VM-26 to their o-Quione derivatives and catalyze the binding of reactive intermediates to DNA. We have shown that both the dihydroxy and o-Quione derivatives are cytotoxic and induce topo-II-dependent cleavage. The binding sites on the topo-II-DNA complex for these O-demethylated drugs are similar to those of the parent compound. We have also shown that the dihydroxy VP-16 binds metal ions (iron and copper). These metal ion complexes are redox-active and induce DNA strand scission in an oxygen- dependent pathway. Recent studies to evaluate mechanisms of VP-16 resistance in a number of tumor cell lines suggest that overexpression and differential effects of VP-16 on c-myc and c-jun may play some roles in drug resistance. Furthermore, overexpressions of both c-myc and bcl2 in resistant cells may be important far resistance and cell survival.